WO2014202760A2 - Vacuum expanded dry composition and syringe for retaining same - Google Patents

Vacuum expanded dry composition and syringe for retaining same Download PDF

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Publication number
WO2014202760A2
WO2014202760A2 PCT/EP2014/063041 EP2014063041W WO2014202760A2 WO 2014202760 A2 WO2014202760 A2 WO 2014202760A2 EP 2014063041 W EP2014063041 W EP 2014063041W WO 2014202760 A2 WO2014202760 A2 WO 2014202760A2
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WO
WIPO (PCT)
Prior art keywords
paste
less
pressure
mbar
dry composition
Prior art date
Application number
PCT/EP2014/063041
Other languages
English (en)
French (fr)
Other versions
WO2014202760A3 (en
Inventor
Kristian Larsen
Michael Wrang Mortensen
Original Assignee
Ferrosan Medical Devices A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to BR112015030612-8A priority Critical patent/BR112015030612B1/pt
Priority to JP2016520511A priority patent/JP6390873B2/ja
Priority to US14/895,674 priority patent/US9724078B2/en
Priority to AU2014283170A priority patent/AU2014283170B2/en
Priority to CN201480035341.0A priority patent/CN105358071B/zh
Priority to EP14734064.0A priority patent/EP3010419B1/en
Application filed by Ferrosan Medical Devices A/S filed Critical Ferrosan Medical Devices A/S
Priority to RU2016101631A priority patent/RU2700162C2/ru
Priority to CA2912357A priority patent/CA2912357C/en
Publication of WO2014202760A2 publication Critical patent/WO2014202760A2/en
Publication of WO2014202760A3 publication Critical patent/WO2014202760A3/en
Priority to HK16109479.3A priority patent/HK1221388A1/zh
Priority to US15/639,237 priority patent/US10595837B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/00491—Surgical glue applicators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0028—Polypeptides; Proteins; Degradation products thereof
    • A61L26/0038—Gelatin
    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0052—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
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    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0066—Medicaments; Biocides
    • A—HUMAN NECESSITIES
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    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
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    • A61M39/22—Valves or arrangement of valves
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    • A61M5/2448—Ampoule syringes, i.e. syringes with needle for use in combination with replaceable ampoules or carpules, e.g. automatic comprising means for injection of two or more media, e.g. by mixing
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    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
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    • A61M5/28—Syringe ampoules or carpules, i.e. ampoules or carpules provided with a needle
    • A61M5/284—Syringe ampoules or carpules, i.e. ampoules or carpules provided with a needle comprising means for injection of two or more media, e.g. by mixing
    • A—HUMAN NECESSITIES
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    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/3129—Syringe barrels
    • A61M5/3135—Syringe barrels characterised by constructional features of the proximal end
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A—HUMAN NECESSITIES
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A61L2300/254—Enzymes, proenzymes
    • A—HUMAN NECESSITIES
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising agents
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    • A61L2400/00—Materials characterised by their function or physical properties
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    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
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    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
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    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
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    • A61M5/3129—Syringe barrels
    • A61M2005/3132—Syringe barrels having flow passages for injection agents at the distal end of the barrel to bypass a sealing stopper after its displacement to this end due to internal pressure increase

Definitions

  • Figure 1 Average reconstitution time +/- standard deviation of the standard freeze- dried gelatine pastes comprising different polyols of example 1 , which have not been vacuum expanded. Inclusion of different polyols in the freeze-dried paste composition resulted in spontaneous reconstitution of the pastes within about 30 seconds.
  • Figure 2. Average reconstitution time +/- standard deviation of the standard lyophilised and vacuum expanded lyophilised gelatine pastes of example 3. Vacuum expansion greatly decreased the spontaneous reconstitution time of pastes comprising mannitol.
  • Figures 3 to 14 depict different embodiments and stages of the method of the present disclosure.
  • Figure 3 shows two possible embodiments of a syringe for use as a container before the paste has been added.
  • Concept 1 encompasses a standard single use syringe and concept 2 encompasses a single use syringe with a lyophilisation bypass in the syringe body. The pressure valve is closed.
  • Figur 19b shows a frontal view of another embodiment of the pressure chamber of the presently disclosed syringe with the pressure valve from fig. 19a.
  • Figures 19c-d show cut-through frontal view of the configuration of the pressure valve from fig. 19a inside the pressure chamber from fig. 19b.
  • Steps c) to d) may conveniently be performed directly in the freeze-dryer as one continuous process.
  • suitable containers holding the paste of step b) may be placed in a freeze-dryer, wherein the paste is expanded by low vacuum, frozen to fix the expanded paste structure and freeze-dried until dry.
  • Figures 3 to 14 show different embodiments of the process steps.
  • the invention relates to a method for preparing a dry composition suitable for use in haemostasis and/or wound healing comprising the sequential steps of:
  • Bioactive agents which are unstable in solution may be added to the paste prior to drying and will thus be present in the dry composition of the invention.
  • thrombin may be added to the paste prior to drying, thereby avoiding the time-consuming and error-prone thrombin dilution steps.
  • the biocompatible polymer of the present disclosure may be a biologic or a non- biologic polymer.
  • Suitable biologic polymers include proteins, such as gelatin, collagen, albumin, hemoglobin, casein, fibrinogen, fibrin, fibronectin, elastin, keratin, and laminin; or derivatives or combinations thereof. Particularly preferred is the use of gelatin or collagen, more preferably gelatin.
  • Other suitable biologic polymers include
  • polyacrylamides polyvinyl resins, polylactide- glycolides, polycaprolactones, and polyoxyethylenes; or derivatives or combinations thereof. Also combinations of different kinds of polymers are possible.
  • the period of time for cross-linking may be optimised by a skilled person and is normally a period between about 10 minutes to about 12 hours, such as about 1 hour to about 10 hours, for example between about 2 hours to about 10 hours, such as between about 4 hours to about 8 hours, for example between about 5 hours to about 7 hours, such as about 6 hours.
  • the polymer has been cross-linked by chemical means, i.e. by exposure to a chemical cross-linking agent.
  • suitable chemical cross- linking agents include but are not limited to aldehydes, in particular glutaraldehyde and formaldehyde, acyl az ' ide, caboiimides, hexamethylene diisocyanate, polyether oxide, 1 ,4-butanedioldiglycidyl ether, tannic acid, aldose sugars, e.g. D-fructose, genipin and dye-mediated photo-oxidation.
  • Specific compounds include but are not limited to l-(3- dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (EDC), dithiobis(propanoic dihydrazide) (DTP), l-ethyl-3-(3-dimethylamino-propyl)-carbodiimide (EDAC).
  • EDC dimethylaminopropyl-3-ethylcarboiimide hydrochloride
  • DTP dithiobis(propanoic dihydrazide)
  • EDAC l-ethyl-3-(3-dimethylamino-propyl)-carbodiimide
  • the agent in powder form comprises or consists of cross-linked gelatine particles obtained from a gelatine hydrogel.
  • a gelatine hydrogel may be prepared by dissolving an amount of gelatine in an aqueous buffer to form a non-cross- linked hydrogel, typically having a solids content from 1 % to 70% by weight, usually from 3% to 10% by weight.
  • the gelatin is cross-linked, for example by exposure to either glutaraldehyde (e.g. 0.01 % to 0.05% w/w, overnight at 0 DEG to 15 DEG C. in aqueous buffer), sodium periodate (e.g. 0.05 M, held at 0 DEG C. to 15 DEG C.
  • EDC 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide
  • EDC 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide
  • the resulting crosslinked hydrogels may be fragmented and dried to obtain a gelatine powder.
  • the average particle diameter is between 1 ⁇ and 1000 ⁇ , such as between 10 ⁇ and 800 ⁇ , for example between 50 ⁇ and 600 ⁇ , such as between 100 ⁇ and 500 ⁇ , for example between 200 ⁇ and 400 ⁇ , such as about 300 ⁇ .
  • the average particle diameter is less than 100 ⁇ , such as less than 50 ⁇ , for example less than 30 ⁇ , such as less than 20 ⁇ , for example less than 10 ⁇ .
  • a smoother paste is desirable is in the control of bone bleeding.
  • the paste of the present disclosure comprises more than 10% of the biocompatible polymer, such as more than 15% of the biocompatible polymer, for example more than 16% of the biocompatible polymer, such as more than 17% of the biocompatible polymer, for example more than 18% of the biocompatible polymer, such as more than 19% of the biocompatible polymer, for example more than 20% of the biocompatible polymer.
  • the paste of the present disclosure comprises less than 40% of the biocompatible polymer, such as less than 30% of the biocompatible polymer, for example less than 25% of the biocompatible polymer, such as less than 20% of the biocompatible polymer.
  • the composition after drying comprises between about 40% and 80% of the biocompatible polymer, such as between about 45% and 75% of the biocompatible polymer, for example between about 50% and 70% of the biocompatible polymer.
  • An aqueous medium is used in the methods of the present disclosure for initially preparing the paste, which is subsequently vacuum expanded and dried, and for reconstituting the dried paste.
  • the aqueous medium may also be a buffered aqueous medium suitable for use in a haemostatic paste.
  • Any suitable buffering agent known to a person of skill may be used, such as one or more buffering agents selected from the group consisting of: Sodium citrate; Citric acid, Sodium citrate; Acetic acid, Sodium acetate; K2HP04, KH2P04; Na2HP04, NaH2P04; CHES; Borax, Sodium hydroxide; TAPS; Bicine; Tris; Tricine;TAPSO; HEPES; TES; MOPS; PIPES; Cacodylate; SSC; MES, or others.
  • the pH of the buffered aqueous medium should be suitable for creating a haemostatic paste intended for human use and can be determined by the skilled person.
  • the aqueous medium is mixed with the agent in powder form in sufficient amounts to obtain a wet paste.
  • the paste prior to drying contains less water, i.e. is thicker, than a paste intended for e.g. surgical use so that less water has to be removed in the drying process.
  • the hydrophilic polymer is selected from the group consisting of Polyethylenimine (PEI), Poly(ethylene glycol) (PEG), Poly(ethylene oxide), Polyvinyl alcohol) (PVA), Poly(styrenesulfonate) (PSS), Poly(acrylic acid) (PAA), Poly(allylamine hydrochloride) and Polyvinyl acid).
  • the hydrophilic compound is PEG.
  • Polyoxyethylene Castor Oil Derivatives Polyoxyethylene Sorbitan Fatty Acid Esters, Polyoxyethylene Stearates, Polyvinyl Alcohol, Sodium Lauryl Sulfate, Sorbitan Esters (Sorbitan Fatty Acid Esters) and Tricaprylin.
  • the dry composition comprises two polyols, for example mannitol and glycerol or trehalose and a glycol.
  • the dry composition comprises one or more sugar alcohols, such as one or more sugar alcohols selected from the group consisting of Glycol, Glycerol, Erythritol, Threitol, Arabitol, Xylitol, Ribitol, Mannitol, Sorbitol, Dulcitol, Fucitol, Iditol, Inositol, volemitol, Isomalt, Maltitol, Lactitol, Polyglycitol.
  • sugar alcohols such as one or more sugar alcohols selected from the group consisting of Glycol, Glycerol, Erythritol, Threitol, Arabitol, Xylitol, Ribitol, Mannitol, Sorbitol, Dulcitol, Fucitol, Idito
  • the dry composition comprises glycol, such as propylene glycol.
  • the paste according to the invention prior to drying comprises from about 4% to about 40% of one or more polyols, for example from about 4% to about 30% of one or more polyols, such as from about 4% to about 25% of one or more polyols, for example from about 4% to about 20% of one or more polyols, such as from about 4% to about 18% of one or more polyols, for example from about 4% to about 17% of one or more polyols, such as from about 4% to about 16% of one or more polyols, for example from about 4% to about 15% of one or more polyols, such as from about 4% to about 14% of one or more polyols, for example from about 4% to about 13% of one or more polyols, such as from about 4% to about 12% of one or more polyols, for example from about 4% to about 1 1 % of one or more polyols, such as about 4% to about 10% of one or more polyols.
  • the paste according to the invention prior to drying comprises from about 6% to about 40% of one or more hydrophilic compounds, for example from about 6% to about 30% of one or more hydrophilic compounds, such as from about 6% to about 25% of one or more hydrophilic compounds, for example from about 6% to about 20% of one or more hydrophilic compounds, such as from about 6% to about 18% of one or more hydrophilic compounds, for example from about 6% to about 17% of one or more hydrophilic compounds, such as from about 6% to about 16% of one or more hydrophilic compounds, for example from about 6% to about 15% of one or more hydrophilic compounds, such as from about 6% to about 14% of one or more hydrophilic compounds, for example from about 6% to about 13% of one or more hydrophilic compounds, such as from about 6% to about 12% of one or more hydrophilic compounds, for example from about 6% to about 1 1 % of one or more hydrophilic compounds, such as about 6% to about 10% of one or more hydrophilic compounds.
  • the paste according to the invention prior to drying comprises more than about 1 % of one or more hydrophilic compounds, such as more than about 2% of one or more hydrophilic compounds, for example more than about 3% of one or more hydrophilic compounds, such as more than about 4% of one or more hydrophilic compounds, for example more than about 5% of one or more hydrophilic compounds, such as more than about 6% of one or more hydrophilic compounds, for example more than about 7% of one or more hydrophilic compounds, such as more than about 8% of one or more hydrophilic compounds, for example more than about 9% of one or more hydrophilic compounds, such as more than about 10% of one or more hydrophilic compounds.
  • one or more hydrophilic compounds such as more than about 2% of one or more hydrophilic compounds, for example more than about 3% of one or more hydrophilic compounds, such as more than about 4% of one or more hydrophilic compounds, for example more than about 5% of one or more hydrophilic compounds, such as more than about 6% of one or more hydrophil
  • the dry composition comprises from about 15% to about 60% of one or more hydrophilic compounds, such as from about 15% to about 50% of one or more hydrophilic compounds, for example from about 15% to about 50%, such as from about 15% to about 45% of one or more hydrophilic compounds, for example from about 15% to about 40%, such as from about 15% to about 35% of one or more hydrophilic compounds, for example from about 15% to about 30% of one or more hydrophilic compounds.
  • the dry composition comprises from about 20% to about 60% of one or more hydrophilic compounds, such as from about 20% to about 50% of one or more hydrophilic compounds, for example from about 20% to about 50%, such as from about 20% to about 45% of one or more hydrophilic compounds, for example from about 20% to about 40%, such as from about 20% to about 30% of one or more hydrophilic compounds.
  • hydrophilic compounds such as from about 20% to about 50% of one or more hydrophilic compounds, for example from about 20% to about 50%, such as from about 20% to about 45% of one or more hydrophilic compounds, for example from about 20% to about 40%, such as from about 20% to about 30% of one or more hydrophilic compounds.
  • the hydrophilic compounds:biocompatible polymer ratio is between about 0.1 :1 and 1 :1 ; such as between about 0.2:1 and 1 :1 , for example between about 0.3:1 and 1 :1 , such as between about 0.4:1 and 1 :1 .
  • the hydrophilic compounds:biocompatible polymer ratio is between about 0.1 :1 and 0.8:1 ; such as between about 0.1 :1 and 0.7:1 , for example between about 0.1 :1 and 0.6:1 , such as between about 0.1 :1 and 0.5:1 , for example between 0.1 :1 and 0.45:1 .
  • Trehalose Tris base cyclodextrin ( ⁇ ⁇ - ⁇ -CD)
  • the dry composition of the present disclosure comprises one or more antimicrobial agents, such as one or more antibacterial agents.
  • the dry composition of the present disclosure does not comprise an antimicrobial agent.
  • the dry composition further comprises an extrusion enhancer, i.e. a compound capable of facilitating extrusion of a paste from a syringe.
  • extrusion enhancers such as albumin in an appropriate amount
  • the amounts are preferably high enough so as to obtain the extrusion effect, i.e. to enable a flowable paste even for relatively high amounts of the biocompatible polymer, e.g. cross-linked gelatine, so that the haemostatic paste composition can be accurately applied by a surgeon using e.g. a syringe comprising an applicator tip; on the other hand, the amounts shall be as low as to prevent negative functional properties of the haemostatic composition.
  • the extrusion enhancer is preferably albumin, especially human serum albumin.
  • the reconstituted wet paste compositions according to the present invention have a mean extrusion force (e.g. by employing the test method described in example 1 of WO 2013/060770) of 40 N or below, preferably below 35 N, especially preferred below 30 N or even below 20 N.
  • a mean extrusion force e.g. by employing the test method described in example 1 of WO 2013/060770
  • phospholipids such as phosphatidylcholine and -serine, or complex mixtures such as lecithins or soy bean oils.
  • the dry composition comprises one or more bioactive agents, i.e. one or more bioactive agents are included in the paste prior to expansion and drying. It is essential that the bioactive agent retains its bioactivity throughout the process, i.e. that the agent has retained its biological function in the final reconstituted paste. Many bioactive agents are unstable in solution, particularly enzymes and other proteins that may be degraded or lose their secondary structure when water is present.
  • the bioactive agent stimulates wound healing and/or haemostasis, such as thrombin.
  • Thrombin may be added to the paste of the present disclosure prior to drying in an amount sufficient to ensure effective haemostasis of the reconstituted dry composition.
  • thrombin is added at a concentration in the range of about 100 lU/ml paste to about 500 lU/ml paste, such as about 150 lU/ml paste to about 450 lU/ml paste, for example about 200 lU/ml paste to about 400 lU/ml paste, such as about 250 lU/ml paste to about 350 lU/ml paste.
  • the dry composition comprises one or more bioactive agents that stimulate bone and/or tendon and/or tissue healing such as one or more growth factors selected from the group consisting of matrix metalloproteinases (MMPs), insulin-like growth factor 1 (IGF-I), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and transforming growth factor beta (TGF- ⁇ ).
  • MMPs matrix metalloproteinases
  • IGF-I insulin-like growth factor 1
  • PDGF platelet-derived growth factor
  • VEGF vascular endothelial growth factor
  • bFGF basic fibroblast growth factor
  • TGF- ⁇ transforming growth factor beta
  • the dry composition comprises one or more Bone Morphogenetic Proteins (BMPs). Bone morphogenetic proteins (BMPs) are a subgroup of the TGF- ⁇ superfamily.
  • IGF-1 increases collagen and proteoglycan production during the first stage of inflammation
  • PDGF is also present during the early stages after injury and promotes the synthesis of other growth factors along with the synthesis of DNA and the proliferation of cells.
  • the three isoforms of TGF- ⁇ (TGF- ⁇ , TGF ⁇ 2, TGF ⁇ 3) are known to play a role in wound healing and scar formation.
  • VEGF is well known to promote TGF- ⁇
  • sympathomimetics xanthine derivatives
  • cardiovascular preparations including calcium channel blockers and beta-blockers such as pindolol and antiarrhythmics;
  • the obtained paste is then transferred into a container suitable for vacuum expansion, freezing and drying of the paste.
  • the container into which the paste is transferred is also suitable for reconstituting and applying the reconstituted paste composition, e.g. to a site requiring hemostasis.
  • the containers may be made from any suitable material such as plastic, glass, ceramic or metal, such as stainless steel.
  • a product chamber comprising a dry composition capable of forming a paste upon addition of an aqueous medium, wherein the pressure within the product chamber is less than the pressure outside the product chamber, and b. a valve.
  • the dry composition reconstitutes spontaneously upon addition of an aqueous medium to the dry composition being present in the container.
  • the container does not comprise a bypass, gaseous
  • One embodiment of the present disclosure relates to a syringe for retaining a freeze- dried paste, such as the presently disclosed dry paste composition, in a vacuum comprising a barrel comprising a vacuum chamber for containing the paste having an open proximal end and a distal end having a first fluid opening, a connector portion having a second fluid opening and adapted for connection to a liquid receptacle, and a pressure chamber connecting the connector portion and the distal end of the vacuum chamber, a pressure valve located in the pressure chamber and adapted to seal the first and/or second fluid openings in a first position and form a fluid passageway between the first and second fluid openings in a second position, a plunger configured to be axially displaced in the vacuum chamber through the open proximal end, and one or more vacuum bypass channels.
  • a syringe for retaining a freeze- dried paste, such as the presently disclosed dry paste composition
  • the barrel may be provided with a flange at the proximal end of the vacuum chamber in order to ease handling of the syringe when operating the plunger. Furthermore, he inside volume of the vacuum chamber and/or the pressure chamber may
  • the pressure chamber comprises a proximal end abutting the distal end of the vacuum chamber and a distal end abutting a proximal end of the connector portion.
  • the connector portion may comprise a proximal end abutting a distal end of the pressure chamber and a distal end adapted for connection to a liquid receptacle.
  • the second fluid opening may form an elongated channel through the connector portion, e.g. as illustrated in figs. 18 and 20.
  • the second fluid opening may comprise a proximal end abutting a distal end of the pressure chamber and a distal end for inlet and outlet of fluid.
  • the pressure valve may be adapted to seal a distal end of the first fluid opening and a proximal end of the second fluid opening in said first position.
  • the liquid for reconstitution of a paste in the vacuum chamber can be provided from the distal end of the syringe, via the second fluid opening in the connector portion and through the pressure chamber and into the vacuum chamber. Delivery of the reconstituted paste is also provided through the distal end of the syringe.
  • an external liquid receptacle may be connected to the connector portion of the syringe while the pressure valve is in the first position, i.e. the fluid passageway is blocked (sealed). Switching the pressure valve to the second position opens the fluid passageway and liquid can pass from the liquid receptacle to the vacuum chamber of the syringe for reconstitution of the paste.
  • the presently disclosed syringe is therefore safe, easy and quick to use when reconstituting a dry paste, such as a haemostatic paste.
  • the limitation may also be provided by means of a narrowing of an inner side wall of the pressure chamber and this narrowing may be adapted to limit a radial displacement of the pressure valve in the first position, e.g. this narrowing may be adapted to match one or more protrusions of the pressure valve, such that this or these protrusions abuts the narrowing in the first position of the pressure valve.
  • a narrowing may be provided by means of one or more "shoulders" of an inner side wall of the pressure chamber, as exemplary illustrated in figs. 19c and 19d.
  • the presently disclosed syringe is preferably configured such that the dry paste composition may be freeze dried inside the vacuum chamber.
  • Said one or more vacuum bypass channels may be configured to provide a fluid, such as a gaseous, communication between the vacuum chamber and the surroundings / the ambient atmosphere, i.e. the vacuum bypass channel(s) may function as the lyophilisation bypass channel as described herein.
  • the syringe is configured such that the plunger sealably engages the vacuum chamber in at least a first axial position of the plunger inside the vacuum chamber, and such that fluid communication is established across the plunger in at least a second axial position of the plunger inside the vacuum chamber via said one or more vacuum bypass channels. I.e.
  • a vacuum can be established and the composition can be freeze dried in the second position of the plunger, whereas the vacuum in the vacuum chamber can be retained in the first position of the plunger.
  • said one or more vacuum bypass channels are configured such that a fluid communication can be provided directly between the vacuum chamber and the ambient atmosphere independent of the position of the plunger, e.g. via a (second) pressure valve located directly at the vacuum chamber.
  • said one or more vacuum bypass channels may be formed in the plunger.
  • the one or more vacuum bypass channels may be configured to break the sealing between the vacuum chamber and the plunger at a predefined axial position of the plunger inside the vacuum chamber.
  • said one or more vacuum bypass channels may be formed in the vacuum chamber.
  • said one or more vacuum bypass channels may be one or more longitudinal grooves formed in the inner surface, e.g. at the proximal end of the vacuum chamber.
  • the vacuum chamber, the pressure chamber and the connector portion may be formed as separate elements and configured to be assembled during manufacture of the syringe.
  • the pressure chamber and the connector portion may be formed as one element and configured to be assembled with the vacuum chamber during manufacture of the syringe.
  • the vacuum chamber and the pressure chamber may be formed as one element and configured to be assembled with the connector portion during manufacture of the syringe.
  • a barrel 1 , 1 ' of the presently disclosed syringe is exemplified in figs. 16-18.
  • the barrel 1 in fig. 16a is provided with a vacuum chamber, a pressure chamber 3, a connector portion 4 and a flange 8 formed in a single piece and suitable for manufacture by single cycle injection moulding.
  • the pressure valve 5 inserted in the pressure chamber 3 is provided with a valve flange 6.
  • fig. 16a the pressure valve is located in a first position whereas in fig. 16b the pressure valve has been displaced to a second position. This is more clearly seen in figs. 16c (first position of pressure valve) and 16d (second position). In the second position of the pressure valve 5 the valve flange 6 abuts the pressure chamber 3.
  • FIG. 18a The cut-through illustrations in fig. 18a and 18b more clearly shows the configuration of the pressure valve 5.
  • the pressure valve blocks the fluid communication between the outlet 1 1 of the internal volume 2' of vacuum chamber 2 and the outlet 7 of the connector portion 4.
  • a fluid communication is provided (as illustrated by the dotted line / arrow) between the surroundings and the internal volume 2' of the vacuum chamber 2 via the pressure chamber 3 and the outlet 7 of the connector portion 4, i.e. liquid can enter the vacuum chamber 2' to mix with a dry composition, e.g. to form a wet paste that subsequently can be controllably released via the outlet 7 by operating a plunger (not shown) arranged in the barrel 1 , 1 '.
  • the barrel 1 ' in fig. 17a does not have a flange.
  • the pressure valve 5 is formed like a cylinder with a circumferential groove 12 that forms the fluid opening in the second position of the pressure valve.
  • the pressure valve 5 is formed like two hollow cylinders that are attached to each other by means of the centrally located rod 13. Even though the rod 13 is located centrally in the fluid passageway, liquid that enters the vacuum chamber 2 via the outlet 7, and paste that is released from the barrel 1 , 1 ' through the outlet 7 can easily pass the rod 13.
  • the pressure valve 5 as illustrated in fig. 18 is rotation symmetric.
  • the connector portion 4 is provided with an internal thread 10, most clearly seen in fig. 18. This may help to provide a secure, tight and tamper-free connection with an external liquid container (having a connector portion with a matching thread) prior to suction of liquid into the vacuum chamber when the (wet) paste is to be formed.
  • Vacuum bypass channels 9 are provided in figs. 16-18 as longitudinally extending grooves in the proximal end of the vacuum chamber 2.
  • the plunger When the plunger (not shown) is arranged in the barrel 1 , 1 ' below these vacuum channels the plunger sealably engages the vacuum chamber.
  • this sealing is not tight, because a fluid, and in particular air, connection is established between the vacuum chamber 2' and the surrounding atmosphere across the plunger via the vacuum bypass channels 9. I.e. during free-drying of paste inside the vacuum chamber 2' suction applied at the proximal end of the barrel can establish a vacuum inside the pressure chamber 2' and thereby expand the dry paste.
  • the plunger can be displaced to a position below the vacuum bypass channels, thereby sealably engaging the vacuum chamber 2 and subsequently retaining the freeze-dried paste in a vacuum.
  • Another exemplary barrel 1 " of the presently disclosed syringe is exemplified in fig. 20 having another embodiment of the pressure valve 5' and the pressure chamber 3' as illustrated in greater detail in fig. 19, with fig. 19a showing a close-up of the pressure valve alone.
  • This pressure valve 5' is slim and provided in a substantially rectangular shape.
  • An aperture 17 forms the fluid passageway in the second position of pressure valve inside the pressure chamber 3'.
  • the outside shape of the pressure valve 5' matches the inside shape of the pressure chamber 3'.
  • 19b shows the pressure valve 5' inside the pressure chamber 3' in the first position of the pressure valve 5', where the fluid passageway is blocked and a vacuum can be retained inside the vacuum chamber 2.
  • the pressure valve 5' is seen to protrude upwards from the pressure chamber 3', i.e. it protrudes radially from the pressure chamber 3' with respect to the longitudinal axis of the barrel 2.
  • the pressure chamber 3' has been cut-through such that the configuration of the pressure valve 5' inside the pressure chamber 3' can be seen.
  • the pressure valve 5' is in the first position, i.e. extending radially from the pressure chamber 3'.
  • the pressure valve 5' and the pressure chamber 3' are configured such that the pressure valve is radially limited in this first position by means of protrusions 14 on the pressure valve 5' that abuts a narrowing 15 of the inner side wall of the pressure chamber 3', i.e. the pressure valve 5' cannot extend further outwards when in the first position. This helps to ensure that the pressure valve 5' is not accidentally removed from the pressure chamber 3' thereby possibly breaking a vacuum sealing inside the vacuum chamber 2.
  • the pressure valve 5' is in the second position.
  • the pressure valve 5' is now completely submerged in the pressure chamber 3'.
  • the rounded top surface of the pressure valve 5' matches a corresponding rounded top surface of the pressure chamber 3' such that the upper surfaces of the pressure valve 5' and the pressure chamber 3' are flush with each other.
  • a stippled arrow in fig. 20a indicates the opening 16 where through the pressure valve 5' can be inserted into the pressure chamber 3'.
  • the barrel 1 " is also suitable for single cycle injection molding. After manufacture the pressure valve 5' can be inserted through the opening 16.
  • the pressure valve 5' in itself is also suitable for single cycle injection molding.
  • the three top holes 18 indicated in figs. 19a and 20c are provided to make the pressure valve 5' suitable for injection molding.
  • the dry composition is in the form of a sheet, i.e. a substantially flat composition.
  • the invention relates to a dry composition in the form of a sheet for use in haemostasis and/or wound healing.
  • the sheet is not pre-wetted before use, i.e. before application to a wound.
  • the sheet will reconstitute in situ on the bleeding wound upon contact with blood, wound exudate, and/or other bodily fluids.
  • the height of the dry sheet composition is in one embodiment between about 0.5 mm and about 10 mm, preferably between about 1 mm and 5 mm, more preferred between about 1 mm and 3 mm, such as about 2 mm.
  • the size (width and depth) of the dry sheet composition depends on the intended use of the sheet and can be selected by the skilled person.
  • the dry sheet material may e.g. be rectangular, square or circular.
  • the dry sheet composition may e.g. be in the form of a rectangle of approximately 5 cm x 10 cm, 2 cm x 6 cm, 6 cm x 8 cm or 8 cm x 12 cm.
  • the dry sheet composition is cut into the desired shape prior to use.
  • the paste is expanded by subjecting the paste to a reduced pressure, i.e. to pressures below ambient pressure, i.e. usually less than 1000 mbar (a low vacuum).
  • a reduced pressure i.e. to pressures below ambient pressure, i.e. usually less than 1000 mbar (a low vacuum).
  • Vacuum expansion results in an increase in the total volume of the paste by expansion of entrapped air or another gas within interstitial pores or compartments of the wet paste.
  • the pressure of the vacuum is selected so that the paste expands to a sufficient degree without collapsing. Thus, the pressure must not be too low, which will result in the paste collapsing. Vacuum expansion of the paste may e.g. be performed in a freeze-dryer.
  • the density of the paste is decreased by about a factor 0.75 as a result of the vacuum expansion.
  • the density of the wet paste may e.g. be in the range of about 0.5 g/ml to about 1 g/ml, such as between about 0.6 g/ml to about 0.9 g/ml, for example between about 0.7 g/ml to about 0.8 g/ml.
  • the density of a gelatine paste prior to expansion is usually within the range of about 0.60 g/ml to about 0.80 g/ml, such as about 0.65 g/ml to about 0.75 g/ml, such as about 0.7 g/ml.
  • the density of the wet paste may e.g. be in the range of about 0.1 g/ml to about 0.8 g/ml, more preferred between about 0.2 g/ml to about 0.7 g/ml, for example about 0.2 g/ml to about 0.6 g/ml, such as about 0.2 g/ml to about 0.5 g/ml.
  • the density of a gelatine paste after expansion is usually within the range of about 0.2 g/ml to about 0.6 g/ml, more preferred between about 0.3 g/ml to about 0.6 g/ml, such as between about 0.4 g/ml to about 0.5 g/ml.
  • the volume of the paste, by subjecting the paste to a reduced pressure, is
  • a factor 1 .05 such as at least a factor 1 .1 , for example at least a factor 1 .2, such as at least a factor 1 .3, for example at least a factor 1 .4, such as at least a factor 1 .5, for example at least a factor 1 .6, such as at least a factor 1 .7, for example at least a factor 1 .8, such as at least a factor 1 .9, for example at least a factor 2.0.
  • a dry vacuum expanded composition comprising gelatine prepared by the method of the present disclosure usually has a density of between about 1 mg/ml to about 40 mg/ml, such as between about 5 mg/ml to about 35 mg/ml, for example between about 10 mg/ml to about 35 mg/ml.
  • the paste is subjected to a reduced pressure of at least 10 mbar less than ambient pressure, for example at least 50 mbar less than ambient pressure, such as at least 100 mbar less than ambient pressure, for example at least 150 mbar less than ambient pressure, such as at least 200 mbar less than ambient pressure, for example at least 250 mbar less than ambient pressure, such as at least 300 mbar less than ambient pressure, for example at least 350 mbar less than ambient pressure, such as at least 400 mbar less than ambient pressure, for example at least 450 mbar less ambient pressure, such as at least 500 mbar less than ambient pressure, for example at least 550 mbar less ambient pressure, such as at least 600 mbar less than ambient pressure, for example at least 650 mbar less ambient pressure, such as at least 700 mbar less than ambient pressure, for example at least 750 mbar less than ambient pressure, such as at least 800 mbar less than ambient pressure, for example at least 850 mbar less than ambient pressure, such as at least 10 mbar
  • the pressure of the vacuum is between less than 1000 mbar and 200 mbar, such as between 1000 mbar and 250 mbar, for example between 1000 mbar and 300 mbar, such as between 1000 mbar and 350 mbar, for example between 1000 mbar and 400 mbar, such as between 1000 mbar and 450 mbar, for example between 1000 mbar and 500 mbar, such as between 1000 mbar and 550 mbar, for example between 1000 mbar and 600 mbar, such as between 1000 mbar and 650 mbar, for example between 1000 mbar and 700 mbar, such as between 1000 mbar and 750 mbar, for example between 1000 mbar and 800 mbar, such as between 1000 mbar and 850 mbar, for example between 1000 mbar and 900 mbar, such as between 1000 mbar and 950 mbar.
  • 1000 mbar and 250 mbar for example between 1000 mbar and 300 mbar, such as between 1000 mbar and 350
  • the expansion rate depends on the vacuum pump and the size of the vacuum chamber, i.e. how fast pressure in the chamber can be decreased to the desired level.
  • the low vacuum levels according to the present disclosure are achieved almost instantaneously, thus expansion of the paste occurs essentially instantaneously after starting the vacuum pump.
  • Vacuum expansion is usually performed at a temperature above the freezing point of the paste.
  • vacuum expansion is performed at ambient temperature or at temperatures below ambient temperature, such as at temperatures of about 0°C to about 25°C, such as at about 2°C to about 20°C, for example about 2°C to about 15°C, such as at about 2°C to about 10°C, such as about 4°C to about 20°C, for example about 4°C to about 15°C, such as at about 4°C to about 10°C.
  • vacuum expansion is preferably performed at temperatures below ambient temperatures. Freezing of the paste
  • the temperature selected for freezing the paste depends on the freezing point of the paste and/or the glass transition temperature of the paste and can be determined by the skilled person.
  • the desired temperature of the frozen paste is approximately 5°C less than the lowest of the freezing point of the paste and the glass transition temperature. E.g. if the freezing point of a paste is -35°C, the paste should be cooled to about -40°C.
  • the haemostatic paste is dried to obtain the dry haemostatic composition.
  • the paste may be dried by any suitable methods known to a person of skill.
  • the paste is freeze-dried. Any suitable freeze-drying technique and equipment known to the person of skill may be used. When freeze- drying is used to prepare the dried paste composition of the present invention, expansion, freezing and drying can advantageously be performed as a continuous process in a single apparatus. Freeze-drying (also known as lyophilisation and cryodesiccation) is a dehydration process typically used to preserve a perishable material or make the material more convenient for transport. Freeze-drying works by freezing the material and then reducing the surrounding pressure to allow the frozen water in the material to sublimate directly from the solid phase to the gas phase.
  • Freeze-drying also known as lyophilisation and cryodesiccation
  • freeze-dryers There are essentially three categories of freeze-dryers: the manifold freeze-dryer, the rotary freeze-dryer and the tray style freeze-dryer. Two components are common to all types of freeze-dryers: a vacuum pump to reduce the ambient gas pressure in a vessel containing the substance to be dried and a condenser to remove the moisture by condensation on a surface cooled to -40 to -80 ' ⁇ .
  • the manifold, rotary and tray type freeze-dryers differ in the method by which the dried substance is interfaced with a condenser. In manifold freeze-dryers a short usually circular tube is used to connect multiple containers with the dried product to a condenser.
  • the rotary and tray freeze- dryers have a single large reservoir for the dried substance.
  • compositions and tissue extracts can be placed in trays, vials and other containers.
  • Manifold freeze-dryers are usually used in a laboratory setting when drying liquid substances in small containers and when the product will be used in a short period of time.
  • a manifold dryer will dry the product to less than 5% moisture content. Without heat, only primary drying (removal of the unbound water) can be achieved.
  • a heater must be added for secondary drying, which will remove the bound water and will produce a lower moisture content.
  • freezing is often done by placing the material in a freeze-drying flask and rotating the flask in a bath, called a shell freezer, which is cooled by mechanical refrigeration, dry ice and methanol, or liquid nitrogen.
  • a freeze-drying machine On a larger scale, freezing is usually done using a freeze-drying machine. In this step, it is important to cool the material below its triple point, the lowest temperature at which the solid and liquid phases of the material can coexist. This ensures that sublimation rather than melting will occur in the following steps. Larger crystals are easier to freeze-dry. To produce larger crystals, the product should be frozen slowly or can be cycled up and down in temperature. This cycling process is called annealing.
  • the freezing is done rapidly, in order to lower the material to below its eutectic point quickly, thus avoiding the formation of ice crystals.
  • the freezing temperatures are between -40 °C and -80 °C.
  • the freezing phase is the most critical in the whole freeze-drying process, because the product can be spoiled if badly done.
  • Amorphous materials do not have a eutectic point, but they do have a critical point, below which the product must be maintained to prevent melt-back or collapse during primary and secondary drying.
  • the pressure is lowered (to the range of a few millibars or less), and enough heat is supplied to the material for the water to sublime.
  • the amount of heat necessary can be calculated using the sublimating molecules' latent heat of sublimation.
  • This phase may be slow (can be several days in the industry), because, if too much heat is added, the material's structure could be altered.
  • pressure is controlled through the application of a medium vacuum. The vacuum speeds sublimation, making it useful as a deliberate drying process.
  • the vapour pressure of water is the pressure at which water vapour is saturated. At higher pressures water would condense.
  • the water vapour pressure is the partial pressure of water vapour in any gas mixture saturated with water.
  • the secondary drying phase aims to remove unfrozen water molecules, since the ice was removed in the primary drying phase.
  • This part of the freeze-drying process is governed by the material's adsorption isotherms.
  • the temperature is raised higher than in the primary drying phase, and can even be above 0 ' ⁇ , to break any physico-chemical interactions that have formed between the water molecules and the frozen material.
  • the pressure is also lowered in this stage to encourage desorption (typically in the range of microbars). However, there are products that benefit from increased pressure as well.
  • the vacuum may be broken with an inert gas, such as nitrogen, before the material is sealed.
  • an inert gas such as nitrogen
  • the vacuum is retained in the product chamber to allow for easy addition of liquid for reconstitution.
  • the final residual water content in the freeze-dried product is in general very low, such as around 2% or lower.
  • the freeze-drying process transforms the paste into a "cake-like" dry composition, which upon addition of an adequate amount of an aqueous medium, such as water, will form a ready-to use paste spontaneously, i.e. no mechanical mixing/reconstitution is required for said paste to form.
  • an aqueous medium such as water
  • the expanded paste is not frozen prior to drying of the paste. Neither is the paste dried by freeze-drying. Rather the low vacuum is upheld while the paste is dried by subjecting the expanded paste to an increased temperature until the paste is dry.
  • the increased temperature is typically in the range of about 30-200°C, such as about 50°C to about 150°C.
  • the method of the present disclosure is a method for preparing a dry composition comprising the steps of:
  • a paste which has been expanded by low vacuum reconstitutes faster than a comparable dry paste composition, which has not been expanded by low vacuum.
  • a paste that has been expanded by vacuum and dried reconstitutes spontaneously to form a substantially homogenous flowable paste without any mechanical mixing.
  • composition being present in a medical delivery device will reconstitute to a ready-to- use paste suitable for direct delivery to a patient without any mechanical mixing required upon addition of an amount of an aqueous medium to the medical delivery device having the dried gelatine paste composition disposed therein.
  • Vacuum expansion expands entrapped air pockets within the paste and such expanded air pockets are retained in the dried paste composition.
  • the presence of larger air pockets in the dry composition enables the wetting of the dry composition due to a larger contact surface area between the dried composition and the liquid. It also facilitates unhindered distribution of the liquid into the dry composition due to the formed channels.
  • the inventors have also discovered that the volume of a paste aliquot is generally higher in samples being aliquoted first as opposed to last from a single batch of paste. This is thought to be due to a partial collapse of the paste occurring over time causing variations in paste density. Such variations in density can lead to undesirable variations in the reconstitution time. Vacuum expansion of the paste prior to drying is able to reduce or even eliminate such "intra-batch" variations in paste density and thus lead to consistently fast reconstitution of the dried pastes. Thus, vacuum expansion provides a higher degree of reproducibility with regards to the reconstitution time.
  • the dry composition may be reconstituted by adding a suitable aqueous medium.
  • the aqueous medium may be added by any suitable mechanism.
  • the aqueous medium is sterile.
  • the aqueous medium is added in an amount sufficient to obtain a wet paste of a desired consistency.
  • the volume of liquid added to the dry composition corresponds essentially to the volume of liquid which was removed by the drying procedure. In case a thinner paste composition is desired, more liquid can be added to the dried paste than was initially removed by the drying procedure.
  • the paste is reconstituted by adding an amount of liquid to a container, such as a medical delivery device, having the dried paste composition disposed therein, even more preferred to the same container which held the paste during the vacuum expansion, freezing and drying steps.
  • the container comprising the reconstitution liquid is essentially free from air or another gas.
  • the advantage of this is that reconstitution is independent of how the containers are oriented in space in relation to each other.
  • there is a vacuum inside the product chamber of the first container i.e. the pressure inside the product chamber of the first container is less than that of the surroundings, i.e. less than atmospheric pressure.
  • the present disclosure relates to a method for reconstituting a dry paste composition comprising the steps of:
  • the second container is a collapsible container such as a plastic bag.
  • the bag collapses due to the pressure difference, thus allowing for liquid flow from the bag to the product chamber and reconstitution of the paste as illustrated in figures 12-13.
  • the second container is a non-collapsible container comprising a plunger, such as a rigid- or semi-rigid plastic container.
  • a plunger such as a rigid- or semi-rigid plastic container.
  • the plunger allows for liquid flow from the aqueous medium container to the product chamber and reconstitution of the paste without exerting manual pressure upon the plunger as illustrated in figures 12-13.
  • a ready-to-use paste forms spontaneously upon addition of liquid to the dry composition disposed within the container within less than about 30 seconds, preferably within less than about 20 seconds, more preferred within less than about 10 seconds, even more preferred within less than about 5 seconds, such as less than about 3 seconds, for example less than about 2 seconds.
  • the reconstituted paste usually requires no further mixing or other forms of manipulations before use.
  • a ready-to-use paste forms within less than about 5 seconds, such as less than about 3 seconds, for example less than about 2 seconds.
  • the container for example a syringe, such as the herein disclosed syringe, may be fitted with an applicator tip suitable for administering the paste in a more precise manner as illustrated in figure 14.
  • the applicator tip is bendable or malleable and will maintain a desired configuration chosen by the user so that it stays at an optimum angle for easy access and exact product placement. Further, it can be cut to a desired length with a pair of nurses dressing scissors or similar type of scissors. These features allow for accurate and convenient application of the paste.
  • the applicator tip is essentially as described in WO 201 1/047753.
  • the dry composition contained within e.g. a syringe, such as the herein disclosed syringe, or other containment unit is further contained within an outer packaging so that the product is kept sterile until use. This will allow the user to remove the outer packaging and transfer the haemostatic composition into a sterile field.
  • a suitable amount of aqueous medium can be added, whereupon a ready-to-use haemostatic paste forms spontaneously within seconds without any need for mechanical agitation, stirring or mixing.
  • the outer packaging is usually made from a flexible, semi-rigid or rigid material and typically consists of materials such as plastic, aluminium foil and/or plastic laminate, where the plastic may be selected from the group consisting of PET, PETG, PE, LLDPE, CPP, PA, PETP, METPET, Tyvek and optionally bonded with an adhesive, such as polyurethane, or co-extruded.
  • the outer packaging is an aluminium foil outer packaging.
  • the outer packaging preferably forms a complete barrier to moisture.
  • the outer packaging is preferably able to endure sterilisation treatment such as by radiation.
  • the dry composition of the present disclosure is preferably sterile. Any suitable sterilisation technique known in the art may be utilised.
  • the sterilisation preferably occurs after the packaging step, i.e. when the dry composition is contained within an outer packaging. Thus, in a preferred embodiment sterilisation is terminal sterilisation.
  • Sterilisation refers to any process that effectively kills or eliminates transmissible agents (such as fungi, bacteria, viruses, prions and spore forms etc.). Sterilisation of the dry composition can be achieved through e.g. application of heat, chemicals, and irradiation.
  • Heat sterilization include autoclaving (uses steam at high temperatures) and dry heat;
  • radiation sterilisation include X-rays, gamma and beta rays, UV light and subatomic particles;
  • chemical sterilisation include using ethylene oxide gas, ozone, chlorine bleach, glutaraldehyde, formaldehyde, ortho phthalaldehyde, hydrogen peroxide and peracetic acid.
  • the dry composition is sterilised by irradiation, e.g. ionizing irradiation, so as to provide sterility to the composition.
  • irradiation may include e- beam (beta irradiation) or gamma irradiation.
  • the level of irradiation and conditions for sterilisation, including the time that the composition is irradiated, are those that provide sterile compositions. Sterilisation conditions are similar to those currently utilized in the preparation of haemostatic loose powders currently available. Once having the benefit of this disclosure, one skilled in the art will be able to readily determine the level of irradiation necessary to provide sterile compositions.
  • sterilisation is usually performed as terminal sterilisation with about 25 kGy or less of beta or gamma irradiation.
  • sterilisation is performed with ethylene oxide.
  • Sterilisation with dry heat may typically be carried out by heating the dry haemostatic composition to a temperature between 100°C and 250°C, such as about 1 10°C to about 200°C.
  • the temperature may be in the range of 1 10-160°C, e.g. in the range of 1 10-140°C, or in the range of 120-180 °C, or in the range of 130-170°C, or in the range of 130-160°C, or in the range of 120-150°C.
  • Heat sterilisation is usually not utilised when the dry composition contains thrombin, since heat treatment would inactivate the thrombin.
  • the dry haemostatic composition is not sterilised after packaging.
  • the product is already sterile when placed in the outer packaging and no further sterilisation is required.
  • the present disclosure relates to a composition produced by aseptic techniques.
  • the present disclosure further relates to use of the paste obtained from the dry composition for promoting haemostasis and/or wound healing.
  • the paste of the present disclosure may e.g. be used in an array of surgical procedures wherein bleeding control is desired.
  • a haemostatic paste conforms to irregular surfaces to stop bleeding fast and it is therefore useful for providing rapid haemostasis on rough or uneven surfaces where haemostatic sponges are not efficient.
  • Haemostatic pastes are prepared directly at the surgical site at the time of need by the medical practitioner, i.e. the doctors or nurses by addition of liquid to a container, such as a syringe, containing an amount of a biocompatible polymer.
  • the biocompatible polymer may be pre-wetted with the liquid or be essentially dry (free-flowing powder).
  • the paste is thus often prepared under extremely stressful conditions and it is therefore essential that the process for preparing the paste is simple and fast to ensure that the bleeding is arrested as quickly as possible and that no mistakes are made while preparing the paste such that the nurse can keep focus on the needs of the surgeon instead of on preparing the haemostat. It is also important that the consistency of the paste is suitable for use as a haemostatic paste and that the consistency of the product is independent from preparation to preparation and over time.
  • the paste of the present disclosure is superior to the currently available flowable products as it reduces or obviates the need for mechanical mixing steps.
  • the paste of the present disclosure may be prepared simply by adding an amount of an aqueous medium to a container comprising the dry composition, whereupon a ready-to-use haemostatic paste forms spontaneously, i.e.
  • the dry composition of the present invention is contained within a medical delivery device under vacuum as described herein, the aqueous medium is automatically drawn into the product chamber due to the pressure difference and the dry composition reconstitutes spontaneously to a ready-to-use flowable composition.
  • the flowable paste can be extruded from the medical delivery device and applied to a patient, e.g. to a bleeding wound, within seconds of coming into contact with the aqueous medium.
  • the quantity of liquid to be added to the dry composition may be adjusted by the skilled person.
  • dry composition of the present invention Another notable advantage of the dry composition of the present invention is that a kit consisting of fewer components can be prepared as compared to e.g. current haemostatic flowable kits. All there is required to prepare a flowable paste composition in the OR is the dry composition as described herein comprised within a medical delivery device and a container comprising an aqueous medium for reconstitution. Upon connection of the two, a ready-to-use flowable paste containing all necessary agents for effective haemostasis including thrombin is formed spontaneously when the aqueous medium is automatically drawn into the vacuum expanded dry composition. Thus, no extra syringes, vial adapters, needles and mixing bowls are required with the product prepared according to the methods of the present disclosure.
  • the present disclosure relates to a method for arresting
  • the paste of the present disclosure may be used for any type of surgery including general surgery, cardiothoracic surgery, vascular surgery, plastic surgery, paediatric surgery, colorectal surgery, transplant surgery, surgical oncology, trauma surgery, endocrine surgery, breast surgery, skin surgery, otolaryngology, gynaecology, oral and maxillofacial surgery, dental Surgery, orthopaedic surgery, neurosurgery,
  • wound refers broadly to injuries to the skin and/or underlying (subcutaneous) tissue initiated in different ways (e.g., pressure sores from extended bed rest and wounds induced by trauma) and with varying characteristics.
  • Wounds may be classified into one of four grades depending on the depth of the wound: i) Grade I: wounds limited to the epithelium; ii) Grade II: wounds extending into the dermis; iii) Grade III: wounds extending into the subcutaneous tissue; and iv) Grade IV (or full-thickness wounds): wounds wherein bones are exposed (e.g., a bony pressure point such as the greater trochanter or the sacrum).
  • the present disclosure relates to treatment of any type of wound mentioned above using the paste of the present disclosure.
  • the treatment of a wound can in principle result in healing of the wound or in accelerated healing of the wound.
  • the accelerated healing can be a result of e.g. administration of a wound-healing promoting substance.
  • the wound healing can be promoted by preventing bacterial or viral infection, or by reducing the risk of such an infection which would otherwise have prolonged the wound treatment process.
  • the present disclosure relates to a method for promoting bone and/or tendon healing in an individual in need thereof by application of the paste of the present disclosure to the injured bone/tendon.
  • the "individual” referred to herein may be any mammal, including, but not limited to, mammals of the order Rodentia, such as mice and hamsters, and mammals of the order Logomorpha, such as rabbits. It is preferred that the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs). It is more preferred that the mammals are from the order Artiodactyla, including Bovines (cows) and Swines (pigs) or of the order Perssodactyla, including Equines (horses). It is most preferred that the mammals are of the order Primates, Ceboids, or Simoids (monkeys) or of the order Anthropoids (humans and apes).
  • an especially preferred mammal is the human.
  • the present disclosure relates to a vacuum expanded, freeze-dried paste, such as the presently disclosed dry composition, for use in the treatment of a wound, e.g. for arresting bleeding or for promoting wound healing.
  • the present disclosure further relates to a haemostatic kit comprising the dry composition of the present disclosure and an amount of aqueous medium matched to the amount of the dry composition so that upon addition of the aqueous medium, a haemostatic paste of a consistency suitable for use as a haemostatic paste will form spontaneously, i.e. within seconds.
  • the present disclosure relates to a haemostatic kit comprising:
  • the present disclosure relates to a haemostatic kit comprising: a) the presently disclosed syringe comprising a dry composition
  • the aqueous medium used to reconstitute the paste may e.g. be selected from water, saline, a calcium chloride solution or a buffered aqueous solution.
  • the aqueous medium used to reconstitute the dry composition is water.
  • the isotonicity of the aqueous medium is selected so that an isotonic paste will form upon addition of the aqueous medium to the dry composition.
  • the aqueous medium used to reconstitute the dry composition is saline or a calcium chloride solution.
  • the dry composition comprises thrombin.
  • the kit further comprises one or more applicator tips.
  • the kit may optionally contain instructions for use of the kit.
  • the resulting paste was filled into 10 ml single use plastic syringes (5.5 ml per syringe) comprising a lyophilisation bypass channel and placed at -30 ⁇ for minimum 4 h.
  • the frozen paste was transferred to the freeze-dryer and freeze-dried until dry for approximately 15 h.
  • the shelves of the lyophiliser were collapsed, thereby moving the plunger and closing the lyo bypass channel.
  • the pressure in the lyophiliser chamber was then brought to ambient pressure leaving a vacuum in the product chamber.
  • the dry haemostatic composition was reconstituted by connecting the syringe comprising the dry composition to a collapsible plastic bag containing water (8 ml ). No mechanical mixing or stirring was used.
  • the water was added to the dry composition by utilising the vacuum inside the product chamber, and the composition was left untouched until a paste was re-formed.
  • the vacuum inside the product chamber of the syringe causes the water to be automatically drawn into the syringe from the container holding the water.
  • Pastes comprising different polyols were made, dried and reconstituted according to the directions above. The contents of the pastes are shown in the tables below.
  • the polyohgelatine ratio in the dry compositions was approximately 0.4:1 .
  • the experiment shows that different kinds of polyols can be used for making a freeze- dried gelatine paste that will reconstitute spontaneously upon addition of an aqueous medium within less than about 30 seconds.
  • the reconstituted paste has a consistency suitable for direct use as a haemostatic paste.
  • the dried paste had a spontaneous reconstitution time of about 5 seconds.
  • the contents of the paste formulation are specified in the table below in the paste (wet) and the dried composition (dry) respectively.
  • the total polyol concentration, i.e. mannitol and glycerol, in the paste was 13.56% and after drying 42.27%.
  • the polyohgelatine ratio in the dry composition was approximately 0.75:1 .
  • the paste was dried by freeze-drying and reconstituted as described in Example 1 .
  • the thrombin activity was measured in the reconstituted paste. The results are shown in the table below.
  • Example 1 The prepared pastes were either freeze dried directly as described in Example 1 (standard lyophilisation) or subjected to a low vacuum of about 850 mbar, followed by a freezing step to - 40°C without releasing the vacuum and finally freeze dried essentially as described in Example 1 (vacuum expanded lyophilisation). Vacuum expansion was performed at ambient temperature, i.e. about 20°C. Upon exposure of the pastes to the decreased pressure, i.e. vacuum, the pastes expanded in volume almost
  • the lyophilised products were reconstituted essentially as described in Example 1 by adding 5.5 ml saline to the lyophilised product and the amount of time for the paste to fully absorb the saline was measured.
  • the vacuum inside the product chamber of the syringes automatically draws in the liquid.
  • Both vacuum expanded and standard pastes were soft and moist after reconstitution and exhibited comparable absorption capacities.
  • the consistency of the reconstituted pastes was considered suitable for direct use on a patient.
  • the reconstituted pastes had a slightly off white/ yellowish colour.
  • Gelatine pastes comprising mannitol were prepared as described in Examples 1 and 3.
  • the pastes were vacuum expanded using different vacuum levels (1000 mbar (no vacuum), 850 mbar and 600 mbar) and then frozen and freeze-dried as described in Example 3.
  • the dry compositions reconstituted spontaneously to form soft and moist pastes suitable for haemostatic and/or wound healing use.
  • Example 5 Effect of vacuum expansion and polyol concentration Gelatine pastes comprising different amounts of mannitol (no mannitol, medium mannitol (approx. 3.9%) or high mannitol (approx.. 7.4%)) were prepared essentially as described in Example 1 with the exception that a Virtis Genesis 35 freeze-dryer was used. Portions of paste were aliquoted into 10 ml single-use syringes having vacumm bypass, each syringe receiving 4 g of the paste. The contents of the paste formulation are specified in the table below in the paste (wet) and the dried composition (dry) respectively.
  • Example 1 The prepared pastes were either freeze dried directly as described in Example 1 (no expansion) or vacuum expanded by exposure to a low vacuum of about 850 mbar, followed by a freezing step to - 40°C without releasing the vacuum and finally freeze dried essentially as described in Example 1 (vacuum expansion). Vacuum expansion was performed at ambient temperature, i.e. about 20°C.
  • Dried vacuum-expanded gelatine pastes containing PEG reconstituted about 1 .7 times faster than control (vacuum expanded gelatine paste without any hydrophilic compounds added) and had a superior consistency. The results are shown in figure 22.
  • the inventors have also discovered that the volume of a paste aliquot is generally higher in samples being aliquoted first as opposed to last from a single batch of paste. This is thought to be due to a partial collapse of the paste over time causing undesirable variations in paste density. Such variations in density can lead to undesirable variations in the reconstitution time. Vacuum expansion of the paste prior to drying is believed to be able to reduce or even eliminate such differences in paste density which can occur between the first and the last portions of pastes being aliquoted from a single paste batch.
  • the results show that vacuum expansion before drying greatly improves the reconstitution rate and is able to provide more consistent results with regards to the reconstitution time.
  • the spontaneous reconstitution rate can be further improved by inclusion of increasing amounts of polyols in the dried paste compositions.
  • inclusion of hydrophilic compounds, such as polyols, in the dried paste compositions also improved the consistency of the reconstituted pastes.
  • a method for preparing a dry composition comprising the sequential steps of:
  • the reduced pressure is a pressure of at least 50 mbar less than ambient pressure, such as at least 100 mbar less than ambient pressure, for example at least 150 mbar less than ambient pressure, such as at least 200 mbar less than ambient pressure, for example at least 250 mbar less than ambient pressure, such as at least 300 mbar less than ambient pressure, for example at least 350 mbar less than ambient pressure, such as at least 400 mbar less than ambient pressure, for example at least 450 mbar less ambient pressure, such as at least 500 mbar less than ambient pressure, for example at least 550 mbar less ambient pressure, such as at least 600 mbar less than ambient pressure, for example at least 650 mbar less ambient pressure, such as at least
  • 700 mbar less than ambient pressure for example at least 750 mbar less than ambient pressure, such as at least 800 mbar less than ambient pressure, for example at least 850 mbar less than ambient pressure, such as at least 900 mbar less ambient pressure.
  • the density of the paste is decreased by at least a factor 0.95 as a result of the vacuum expansion, such as at least a factor 0.90, for example at least a factor 0.85, such as at least a factor 0.80, for example at least a factor 0.75, such as at least a factor 0.70, for example at least a factor 0.65, such as at least a factor 0.60, for example at least a factor 0.55, such as at least a factor 0.50 as a result of the vacuum expansion.
  • the agent in powder form is a biocompatible polymer.
  • the method according to any of the preceding items, wherein the agent in powder form is cross-linked.
  • the method according to any of the preceding items, wherein the agent in powder form is biologically absorbable.
  • the method according to any of the preceding items, wherein the agent in powder form is gelatine.
  • the method according to any of the preceding items, wherein the drying is freeze- drying.
  • the method according to any of the preceding items, wherein the drying results in a dry composition comprising less than about 5% water, preferably less than about 2% water.
  • the method according to any of the preceding items, wherein the agent in powder form and the aqueous medium is mixed with one or more hydrophilic compounds.
  • hydrophilic compounds are one or more polyols.
  • glycol selected from the group consisting of glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, dulcitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol and polyglycitol. 18. The method according to any items 15 to 17, wherein the one or more polyols is mannitol and optionally one or more further hydrophilic compounds.
  • dry composition further comprises one or more bioactive agents capable of stimulating
  • aqueous medium is selected from the group consisting of water, saline, a calcium chloride solution and a buffered aqueous medium.
  • the method comprises a further step of placing the dry composition into an outer packaging, such as an aluminium foil packaging.
  • the method comprises a further step of sterilising the dry composition.
  • a wet paste composition being a vacuum expanded wet paste having a density of between about 0.2 g/ml to about 0.6 g/ml, more preferred between about 0.3 g/ml to about 0.6 g/ml, such as between about 0.4 g/ml to about 0.5 g/ml.
  • a dry composition obtainable by the method of any of items 1 to 24.
  • a vacuum chamber for containing the paste having an open proximal end and a distal end having a first fluid opening
  • a connector portion having a second fluid opening and adapted for connection to a liquid receptacle
  • a pressure valve located in the pressure chamber and adapted to seal the first and second fluid openings in a first position and form/create a fluid passageway between the first and second fluid openings in a second position, - a plunger configured to be axially displaced in the vacuum chamber through the open proximal end, and
  • the pressure valve comprises an aperture
  • the aperture forms at least a part of the fluid passageway in the second position of the pressure valve, said aperture preferably extending in the longitudinal direction of the barrel.
  • a container comprising:
  • a product chamber comprising a dry composition capable of forming a paste upon addition of an aqueous medium, wherein the pressure within the product chamber is less than the pressure outside the product chamber, and
  • the container according to item 74 being a syringe, such as a single-use plastic syringe, such as the syringe according to any of items 29 to 73.
  • a method for reconstituting a dry composition comprising the steps of:
  • a method for reconstituting a dry composition comprising the steps of:
  • syringe of any of items 29 to 73 comprising a dry composition capable of forming a paste upon addition of an aqueous medium, wherein the dry composition is located in the vacuum chamber and wherein the pressure within the vacuum chamber is less than the pressure outside the vacuum chamber, and wherein the pressure valve of the syringe is arranged in the first position,
  • the second container comprising the aqueous medium is selected from i) a collapsible container, such a plastic bag, and ii) a non-collapsible container comprising a plunger.
  • a haemostatic kit comprising:
  • a syringe according to any of items 29 to 73 comprising a dry composition b) a container comprising an aqueous medium, and
  • the haemostatic kit according to item 80 wherein the dry composition is a dry composition that is configured to form a haemostatic paste of a consistency suitable for use as a haemostatic paste upon addition of the aqueous medium, such as form spontaneously within seconds.
  • haemostatic kit according to any of items 80 to 81 , wherein the dry composition is obtained by the method of any of items 1 to 24. 83.
  • a haemostatic kit comprising:

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JP2016520511A JP6390873B2 (ja) 2013-06-21 2014-06-20 減圧膨張させた乾燥組成物およびそれを保持するためのシリンジ
US14/895,674 US9724078B2 (en) 2013-06-21 2014-06-20 Vacuum expanded dry composition and syringe for retaining same
AU2014283170A AU2014283170B2 (en) 2013-06-21 2014-06-20 Vacuum expanded dry composition and syringe for retaining same
CN201480035341.0A CN105358071B (zh) 2013-06-21 2014-06-20 真空膨胀的干组合物和用于保留该干组合物的注射器
EP14734064.0A EP3010419B1 (en) 2013-06-21 2014-06-20 Vacuum expanded dry composition and syringe for retaining same
BR112015030612-8A BR112015030612B1 (pt) 2013-06-21 2014-06-20 método para preparar uma composição seca
RU2016101631A RU2700162C2 (ru) 2013-06-21 2014-06-20 Расширенная под вакуумом сухая композиция и шприц для ее сохранения
CA2912357A CA2912357C (en) 2013-06-21 2014-06-20 Vacuum expanded dry composition and syringe for retaining same
HK16109479.3A HK1221388A1 (zh) 2013-06-21 2016-08-09 真空膨脹的干組合物和用於保留該幹干組合物的注射器
US15/639,237 US10595837B2 (en) 2013-06-21 2017-06-30 Vacuum expanded dry composition and syringe for retaining same

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